CN1038449A - Antiarrhythmics - Google Patents

Antiarrhythmics Download PDF

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CN1038449A
CN1038449A CN 88103622 CN88103622A CN1038449A CN 1038449 A CN1038449 A CN 1038449A CN 88103622 CN88103622 CN 88103622 CN 88103622 A CN88103622 A CN 88103622A CN 1038449 A CN1038449 A CN 1038449A
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salt
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indane
amino
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CN1016506B (en
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彼得·爱德华·克罗斯
约翰·爱德蒙·阿罗史密斯
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FIZER Ltd
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FIZER Ltd
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Abstract

Compound that structural formula is following and salt thereof, each R (identical) wherein is-NHSO 2(C 1-C 4Alkyl) ,-NH 2Or-NO 2
X is O or direct key;
R 1Be hydrogen, C 1-C 4Alkyl, C 1-C 4Alkoxy or halogen;
N is 1 or 2, but when X was O, n was 2;
Each R is-NHSO 2(C 1-C 4The compound of structural formula alkyl) (A) is an antiarrhythmics.R is-NH 2Or-NO 2Compound be synthetic intermediate.

Description

Antiarrhythmics
The present invention about some 1,2-indane sulfonamides antiarrhythmics and body wherein.
Antiarrhythmics of the present invention can prolong the action potential extended period in cardiac muscle and conductive tissue, therefore can improve the refractoriness to stimulating before the phase.Like this, according to the sorting technique Anti-Arrhythmic Action of Vaughan Williams, E.M.Vaughan Williams, Academic Press, 1980), they are III class antiarrhythmics.All effective in their atrium, ventricle and conductive tissues in vitro and in vivo, so they are used to prevent and treat various ventricles and supraventricular arrhythmia, comprise atrium and ventricular fibrillation.Because they do not change the conduction of velocity of pulse, therefore to compare with the medicine (mostly being I class medicine) of present usefulness, their quicken or to aggravate ARR proneness less, and the nervosa side effect is also less.Some compound strengthens the effect of myocardial contraction in addition, and is therefore, just more favourable for the patient of myocardium blood-pumping function obstacle.
The invention provides following compound of structural formula and salt thereof:
Figure 881036226_IMG4
Wherein, each R is identical, is-NO 2,-NH 2Or-NHSO 2(C 1-C 4Alkyl);
X is O or direct key;
R 1Be H, C 1-C 4Alkyl, C 1-C 4Alkoxy or halogen;
N is 1 or 2, and when X was O, n was 2.
Each R is-NHSO 2(C 1-C 4The compound of structural formula alkyl) (A) is the arrhythmia medicine.Each R is-NO 2Or-NH 2The compound of structural formula (A) be synthetic intermediate.
Therefore, the invention provides the antiarrhythmic medicine of the salt of following compound of structural formula and useful as drug thereof.
Figure 881036226_IMG5
R wherein 1Be hydrogen, C 1-C 4Alkyl, C 1-C 4Alkoxy or halogen;
Each R 2(being identical) is C 1-C 4Alkyl;
X is O or direct key;
N is 1 or 2, but when X was O, n was 2.
Alkyl is a methyl preferably, and alkoxyl group is a methoxyl group preferably.C 3And C 4Alkyl and alkoxyl group can be straight chain, also can be side chain.Halogen is meant fluorine, chlorine, bromine or iodine.
R 1Hydrogen preferably.
The structural formula of the best antiarrhythmics of structure formula I is as follows:
Figure 881036226_IMG6
The compound of structural formula (A) is optically active, therefore the present invention includes R, S and R/S body.
The salt of the useful as drug of the compound of structure formula I, comprise and the acid salt that acid became that can form the non-toxic acid additive salt, these nontoxic acid salt have the negatively charged ion that can be used for medicine, for example hydrochloride, hydrogen bromide salt, hydriodate, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate, acetate, maleate, fumarate, lactic acid salt, tartrate, Citrate trianion, gluconate, benzoate, mesylate, benzene sulfonate (besylate) and tosilate.Also comprise an alkali metal salt, particularly sodium and sylvite.These salt can prepare with ordinary method.
In order to estimate the effect of these compounds at anterior chamber's refractoriness, right half anterior chamber places a water-bath that normal saline solution is arranged with cavy, and one links to each other with strength sensor.Tissue stimulates with 1 hertz of field plate.Effective refractory period (ERP) stimulates (S by per the 8th basis 1) stimulated (S before the introductory phase afterwards 2) measure.S 1S 2Coupling increases at interval gradually, until S 2Reappear diffusion effect.This just is defined as ERP.Just determine then in order to increase the required compound concentrations ED of 25%ERP 25Measure in the right papillary muscle of the cavy that ERP also can cultivate in physiological saline.Use the bipolar electrode stimulated muscle at one, compose with one pole surface electrode record diffusion electricity in the other end.ERP is with above-mentioned external stimulus technical measurement.Conduction time is stored the oscilloscope from numeral and is obtained, and promptly measures the peak-to-peak interval (stimulating by the required time of muscle length) that stimulates with the electricity spectrum.
Before the room and the also available external stimulus technology of ERP ventricle are measured on one's body anesthesia or clear-headed dog.But atrium or right ventricle will be adjusted to a constant speed.
The compound of formula I can be individually dosed, but general and pharmacy carrier is made the mixture administration.These pharmacy carriers are to put into practice according to the pharmacy of route of administration and standard to select.They can give to have suffered from ARR patient, give to suffer from possibly ARR people with also can giving anti-property.For example, they can make the tablet form of oral administration, the vehicle of starch-containing or lactose class in this tablet; Also can be made into capsule, make separately or make mixture with vehicle; Or with the form of elixir or suspension, elixir and suspension contain correctives or tinting material they also can the outer drug administration by injection of gi tract, for example intravenous injection, intramuscular injection or subcutaneous injection.To the gi tract external administration, they preferably make aseptic aqueous solution, can contain other solutes in this solution, and for example the salt of capacity or glucose ooze solution etc.
For adult patient's (70 kilograms), treating or giving anti-property treatment heart trouble,, comprise when room and chamber property fiber tremble as ventricle and supraventricular arrhythmia, the formula I compound every day oral dosage in the 2-150 nanogram range, can be divided at the most and taking for four times.Every as required single dose is the 1.0-20 milligram during intravenous administration.The best intravenously administrable treatment of serious arrhythmia is so that be corrected to normal rhythm as soon as possible.To a typical adult patient, in each tablet or the capsular carrier that is suitable for medicine, can contain 2-50 milligram active compound.But the medical worker also can do some variations according to the patient's who is treated the body weight and the state of an illness.
Like this, the invention provides a kind of medicinal compositions, this composition comprises the compound of above-mentioned formula I or salt and a kind of diluent or carrier that can be used for medicine of its useful as drug.
The present invention also provides a kind of ARR method that prevents or alleviate the mankind.This method comprises to patient with the compound of the structure formula I of effective dose or the salt of its useful as drug, or medicinal compositions recited above.
The present invention also provides the compound of formula I or the salt of its useful as drug, the application method during as medicine, particularly as antiarrhythmics.
The present invention also provides the salt of the compound of formula I and useful as drug thereof to be used for making to prevent and has alleviated ARR medicine.
The formula I compound can be used C 1-C 4Alkyl sulfonyl chloride or acylbromide or C 1-C 4(in formula (A), each R is-NH the alkylsulphonic acid acid anhydride with formula (A) compound 2) the acidylate preparation.Obviously need two normal acylating agents at least, the R base of product will be identical certainly.
Usually this reaction is at room temperature carried out, and also can carry out these acid acceptors such as pyridine, triethylamine, salt of wormwood or sodium bicarbonate in the presence of acid acceptor.When using alkyl sulfonyl chloride or acylbromide, the existence of acid acceptor is very useful especially.This reaction most convenient is to carry out in pyridine with alkyl sulfonyl chloride.The effect of pyridine is an acid acceptor, is again solvent.The product of formula I can be used conventional method separation and purification then.
(wherein each R is-NH the raw material of formula (A) 2), can (wherein each R be-NO by corresponding compounds 2), with the method for routine as in suitable organic solvent (as ethyl acetate, or ethyl acetate and methanol mixture), use H 2/ P d/ C, reduction preparation under about room temperature.
(wherein each R is-NO the raw material of formula (A) 2) can be prepared as follows:
Q is leavings group such as chlorine, bromine, iodine, mesyloxy, phenylsulfonyloxy or tolysulfonyl oxygen base.Q is a bromine preferably.This reaction generally in organic solvent (as acetonitrile or acetonitrile/ethanol), is carried out under refluxing, and the existence of alkali such as salt of wormwood or sodium bicarbonate also will be arranged simultaneously.
1,2-indane raw material can be by preparing the method preparation that describes in detail among the 1-3.The oil of mirbane raw material that replaces generally says it is compound known, perhaps with preparing with the prior art similar methods described in the following preparation.
When n is 1 or 2, when X was direct key, the following route that has described in detail in the preparation below also can be used for preparing each R and is-NO 2The raw material of formula (A):
（a）〔n＝2〕
(b) (n=1)
Figure 881036226_IMG9
In following example, narrated preparation method's (all temperature be ℃) of the compound of formula I.
Example 1
5-methylsulfonyl amido-2-(N-(2-{ 4-sulfonyloxy methyl amido phenoxy group }-ethyl)-N-methylamino-)-indane
Figure 881036226_IMG10
Methanesulfonyl chloride (0.15 milliliter) is joined 5-amino-2-(N-(2-{ 4-amino-benzene oxygen } ethyl)-N-methylamino-) in the solution of indane (0.25 gram) in pyridine, reaction mixture at room temperature stirred 17 hours.Vacuum is steamed to desolventize and is obtained jelly.This jelly is made column chromatography purification on silicon-dioxide, to contain the methylene dichloride wash-out of methyl alcohol (0-1%).Merge the fraction that contains product, vacuum-evaporation obtains the spumescence title compound, output 0.06 gram.
′H-N.m.r.（CDCl 3）：δ＝7.25（d，2H）;7.2（d，1H）;7.1（s，1H）;7.0（d，1H）;6.95（d，2H）;4.1（t，2H）;3.55（t，1H）;3.1（m，2H）;3.05（s，3H）;3.0（s，3H）;2.9（m，4H）;2.45（s，3H）.
Example 2
5-methylsulfonyl amido-2-(N-(4-sulfonyloxy methyl amido styroyl)-N-methylamino-) indane
Figure 881036226_IMG11
Methylsulfonyl chloride (0.155 milliliter) is joined 5-amino-2-(N-(4-amino-benzene ethyl)-N-methylamino-) in the solution of indane (0.28 gram) in pyridine (30 milliliters), reaction mixture at room temperature stirred 17 hours.Vacuum is steamed to desolventize and is obtained jelly.This jelly is dissolved in the methylene dichloride, with sodium bicarbonate aqueous solution and salt water washing, dry (sal epsom), vacuum-evaporation.Resistates is column chromatography purification on silicon-dioxide, to contain the methylene dichloride wash-out of methyl alcohol (0-2%).Merge the fraction that contains product, vacuum-evaporation generates the spumescence title compound to doing, output 0.27 gram.
Analyze %:
Experimental value: C, 54.5; H, 6.2; N, 9.35;
Calculated value: C 20H 27N 3O 4S 2: C, 54.9; H, 6.2; N, 9.6.
′H-N.m.r.（CDCl 3）：δ＝7.2（q，4H）;7.15（d，1H）;7.1（s，1H）;7.0（d，1H）;3.45（t，1H）;3.05（m，2H）;3.0（d，6H）;2.95（m，2H）;2.90（m，2H）;2.85（m，2H）;2.4（s，3H）.
Example 3
5-methylsulfonyl amido-2-(N-(4-methylsulfonyl amido benzyl)-N-methylamino) indane
Methylsulfonyl chloride (0.53 milliliter) is joined 5-amino-2-(N-(4-aminobenzyl)-N-methylamino) in the solution of indane (1.1 gram) in pyridine.Reaction mixture at room temperature stirred 17 hours.Vacuum is steamed and is desolventized, and resistates is dissolved in the methylene dichloride.With sodium bicarbonate aqueous solution washing, dry (sal epsom), vacuum-evaporation.The jelly column chromatography purification on silicon-dioxide that generates is to contain the methylene dichloride wash-out of methyl alcohol (0-2%).Merge the fraction that contains product, vacuum-evaporation obtains the title thing of colourless foam shape to doing.This foam is dissolved in the chloroform, and vacuum-evaporation obtains colourless foam shape title compound to doing, output 0.2 gram.
Analyze %:
Experimental value: C, 54.0; H, 6.0; N, 9.5;
Calculated value: C 19H 25N 3O 4.2/3CHCl * 3: C, 53.9; H, 5.9; N, 9.6.
*This product be solvate be with nucleus magnetic resonance ( 1H) method calibrating and quantitative.′H-N.m.r.（TFAd）：δ＝7.72（s，1H）;7.63（t，1H）;7.45（d，2H）;7.4（t，2H）;7.3（s，1H）;4.8（d，1H）;4.5（m，1H）;4.35（d，1H）;3.6（m，4H）;3.2（d，6H）;2.9（d，3H）.
In following preparation narration (all temperature all be ℃) preparation of used raw material in the example.
Preparation 1
2-formamido group indane
Figure 881036226_IMG13
With acetic anhydride (40 milliliters) and mixed 50 ℃ of heating, stirring 15 minutes that are incorporated in of formic acid (20 milliliters).Add in the mixture 2-amido dihydro indenes hydrochloride (25 gram) (see J.Med.Chem., 1980,23, P745) and sodium acetate (20 restrain), at room temperature stirred then 24 hours.Reaction mixture is poured in the frozen water, with dichloromethane extraction three times.Merge organic layer, with water and aqueous sodium carbonate washing, dry (MgSO 4).Vacuum-evaporation obtains title compound, output 17.6 grams, fusing point 72-74 °.
Analyze %:
Experimental value: C, 74.25; H, 7.0; N, 8.6;
Calculated value: C 10H 11NO:C, 74.5; H, 6.9; N, 8.7.
′H-N.m.r.（CDCl 3）：δ＝8.0（s，1H）;7.1（s，4H）;4.7（m，1H）;3.4（dd，2H）;2.8（dd，2H）.
Preparation 2
2-formamido group-5-nitro indane
Figure 881036226_IMG14
Temperature is controlled at 0--5 °, and 2-formamido group indane (15 gram) gradation is joined in the nitrosonitric acid (30 milliliters, density=1.5 grams per milliliters).Continue down to stir 1 hour at 0 °, then reaction mixture is poured in the frozen water, use dichloromethane extraction.Organic layer washs with sodium bicarbonate aqueous solution, dry (MgSO 4), vacuum-evaporation obtains oily matter then.Oily matter is column chromatography purification on silicon-dioxide.With the methylene dichloride that contains hexane (20-0%), then with the methylene dichloride wash-out that contains methyl alcohol (0-2%), merge the fraction that contains product, evaporation obtains title compound, output 7.7 grams, fusing point 91-92 °.
Analyze %:
Experimental value: C, 58.1; H, 4.8; N, 13.5;
Calculated value: C 10H 10N 2O 3: C, 58.25; H, 4.9; N, 13.6.
Preparation 3
2-methylamino--5-nitro indane hydrochloride
0-5 ° and stir under, drip acetate (6.4 milliliters) to 2-formamido group-5-nitro indane (4.6 gram) and sodium borohydride (4.22 restrain) in the mixture in tetrahydrofuran (THF) (65 milliliters).Continue to stir 15 minutes at 0-5 °, the reaction of reaction mixture temperature rising reflux is 2 hours then.The vacuum-evaporation reaction mixture is to doing, and resistates is used aqueous sodium carbonate furnishing alkalescence (to pH about 12) then with the dilution of 2M hydrochloric acid, uses dichloromethane extraction.Dry organic layer (MgSO 4), vacuum-evaporation, resistates stirs with ether solution of hydrogen chloride, leaches the precipitation of generation, and drying obtains title compound, output 1.5 grams, fusing point 221-223 °.
Analyze %:
Experimental value: C, 52.75; H, 5.6; N, 12.15;
Calculated value: C 10H 12N 2O 2.HCl:C, 52.5; H, 5.7; N, 12.25.
Preparation 4
2-(N-methyl-N-(2-{ 4-nitrophenoxy } ethyl) amino)-5-nitro indane
Figure 881036226_IMG16
In acetonitrile (50 milliliters)/ethanol (20 milliliters), 2-methylamino--5-nitro indane hydrochloride (0.46 gram), 2-bromine oxethyl-4-oil of mirbane (0.49 gram) (are seen C.A., 54,11046a) and salt of wormwood (2 gram) reflux 20 hours (1960).Vacuum is steamed and is desolventized, and residue diluted with water is used dichloromethane extraction.Dry organic layer (MgSO 4), evaporation obtains oily matter.Oily matter is column chromatography purification on silicon-dioxide, to contain the methylene dichloride wash-out of methyl alcohol (0-1%).Merge the fraction that contains product, evaporation obtains the oily title compound, output 0.28 gram.
′H-N.m.r.（CDCl 3）：δ＝8.0（d，2H）;7.9（m，2H）;7.2（d，1H）;6.8（d，2H）;4.1（t，2H）;3.4（m，1H）;2.9（br d，4H）;2.8（t，2H）;2.3（s，3H）.
Preparation 5
5-amino-2-(N-(2-{ 4-amino-benzene oxygen } ethyl)-N-methylamino-) indane
Under room temperature and hydrogen (206.8 kPas (30 pounds/inch 2)), with 2-(N-methyl-N-(2-{ 4-nitrophenoxy } ethyl) amino)-solution stirring of 5-nitro indane (0.3 gram) in the ethyl acetate (30 milliliters) that contains 5% palladium/charcoal (0.03 gram) 2 hours.Filtration catalizer, vacuum-evaporation filtrate generates gluey title compound, and output 0.25 gram can directly use, not purifying.
Preparation 6
2-(N-methyl-N-(4-oil of mirbane ethyl) amino)-5-nitro indane
Figure 881036226_IMG18
With 2-methylamino--5-nitro indane hydrochloride (0.45 gram), 4-p-ethyl bromide thing (0.46 gram) and salt of wormwood (2 restrain) reflux 3 days in acetonitrile (30 milliliters).Filter reaction mixture then, filtrate vacuum-evaporation.Resistates is column chromatography purification on silicon-dioxide, to contain the methylene dichloride wash-out of methyl alcohol (0-1%).Merge the fraction that contains product, vacuum-evaporation obtains jelly.Jelly is crystallization in ethanol, obtains title compound, output 0.16 gram, fusing point 138-141 °.
Analyze %:
Experimental value: C, 62.8; H, 5.5; N, 12.1;
Calculated value: C 18H 19N 3O 4: C, 63.3; H, 5.6; N, 12.3.
′H-N.m.r.（CDCl 3）：δ＝8.2（d，2H）;8.1（d，1H）;8.05（s，1H）;7.4（d，2H）;7.3（d，1H）;3.5（t，1H）;3.15（q，2H）;2.9（m，4H）;2.8（t，2H）;2.4（s，3H）.
Preparation 7
2-(N-methyl-N-(4-oil of mirbane ethyl) amino) indane hydrochloride
In Dean-Stark(Dean-Rodney Stark moisture determination) device in, 2-hydrindone (2.8 gram), N-methyl-4-oil of mirbane ethamine (3.83 gram) (are seen J.O.C., (1956), 21,45) and the reaction solution reflux of tosic acid (0.1 gram) in toluene (100 milliliters) 1 hour, the water (about 0.4 milliliter) to all generations at this moment collects with azeotropic method.Vacuum is steamed and is desolventized then.Resistates is dissolved in the ethanol (100 milliliters), adds sodium borohydride (0.8 gram) in ethanolic soln, and mixture at room temperature stirred 6 hours.Mixture heating up refluxed 10 minutes then, cooling, and vacuum-evaporation is to doing.Under stirring resistates is added in the 2M hydrochloric acid (150 milliliters), after half an hour, leaches semisolid precipitation.Filtrate obtains title compound with ether washing, drying.Output 1.2 grams, fusing point 201-203 °.
Analyze %:
Experimental value: C, 64.95; H, 6.4; N, 8.4;
Calculated value: C 18H 20N 2O 2.HCl:C, 64.85; H, 6.45; N, 8.3.
′H-N.m.r.（DMSO d 6）：δ＝8.3（d，2H）;7.6（d，2H）;7.2（q，4H）;4.2（quintet，1H）;3.4（m，8H）;2.8（d，3H）.
Preparation 8
(the another kind of method of preparation 6)
2-(N-methyl-N-(4-oil of mirbane ethyl) amino)-5-nitro indane
Figure 881036226_IMG20
In 10 minutes, gradation is with 2-(N-methyl-N-(4-oil of mirbane ethyl) amino) indane hydrochloride (1.2 gram) joins in the nitrosonitric acid (20 milliliters, density=1.5 grams per milliliters) that is chilled to-5 °.Restir 2 minutes is poured reaction mixture in the frozen water into then.The mixture dichloromethane extraction that contains water.Organic extracting solution washs with sodium bicarbonate aqueous solution, dry (MgSO 4), vacuum-evaporation is to doing.Resistates obtains title compound with ethyl alcohol recrystallization, output 0.78 gram, fusing point 138-140 °.
Preparation 9
5-amino-2-(N-(4-amino-benzene ethyl)-N-methylamino-) indane
Figure 881036226_IMG21
(206.8 kPas (30 pounds/inch of room temperature and hydrogen 2)) under, with 2-(N-methyl-N-(4-oil of mirbane ethyl) amino)-solution stirring of 5-nitro indane (0.5 gram) in the ethyl acetate/methanol (40 milliliters/10 milliliters) that 5% palladium/carbon (0.05 gram) arranged 4 hours.Filtration catalizer then, filtrate vacuum-evaporation obtains jelly.Jelly grinds with ether, the ether liquid that comes down in torrents, and vacuum-evaporation obtains title compound to doing, output 0.33 gram.Take out sample, recrystallization in diisopropyl ether, fusing point: 112-114 °.
Analyze %:
Experimental value: C, 76.6; H, 8.3; N, 14.6;
Calculated value: C 18H 23N 3: C, 76.8; H, 8.2; N, 14.9.
′H-N.m.r.（CDCl 3）：δ＝7.05（d，2H）;7.0（d，1H）;6.7（d，2H）;6.55（s，1H）;6.5（d，1H）;3.6（br s，4H）;3.4（quinter，1H）;3.0（m，2H）;2.8（m，2H）;2.7（d，4H）;2.4（s，3H）.
Preparation 10
2-(N-benzyl-N-methylamino-) indane hydrochloride
In Dean and Sfark device, with 2-hydrindone (5.28 gram), N-benzyl methylamine (4.84 gram) and the solution of tosic acid (0.15 gram) in toluene (120 milliliters), reflux 1.5 hours.The water of then all generations (about 0.8 milliliter) all collects with azeotropic method.Vacuum is steamed and is desolventized.Resistates is dissolved in the ethanol (150 milliliters), adds sodium borohydride (1.6 gram), and mixture at room temperature stirred 17 hours.Vacuum is steamed and is desolventized, and resistates is used 2M hydrochloric acid (200 milliliters) dilution carefully.This acid solution extracts twice with methylene dichloride (2 * 100 milliliters), merges organic extracting solution, vacuum-evaporation, and the resistates that obtains grinds with Virahol.Leach the precipitation of generation, drying obtains title compound, output 2.5 grams, 206 ° of fusing point 204-.
Analyze %:
Experimental value: C, 74.1; H, 7.4; N, 5.0;
Calculated value: C 17H 19N.HCl:C, 74.6; H, 7.4; N, 5.1.
′H-N.m.r.（CDCl 3）：δ＝7.7（dd，2H）;7.5（m，3H）;7.15（q，4H）;4.4（q，1H）;4.15（q，1H）;4.05（quintet，1H）;3.8（q，1H）;3.6（q，1H）;3.5（q，1H）;3.25（q，1H）;2.6（d，3H）.
Preparation 11
(the another kind of method of preparation 10)
2-(N-benzyl-N-methylamino-) indane hydrochloride
Figure 881036226_IMG23
With 2-methylamino-indane (0.65 gram) (see J.Med.Chem., 1980,23, P745), cylite (0.6 gram) and salt of wormwood (1.0 restrain) reflux 8 hours in acetonitrile.Filter reaction mixture then, vacuum-evaporation is to doing.The oily matter that generates is dissolved in the ethyl acetate, dilutes with ether solution of hydrogen chloride.Filter collecting precipitation, recrystallization in Virahol obtains title compound, output 0.5 gram, fusing point 204-206 °.
Preparation 12
2-(N-methyl-N-(4-nitrobenzyl) amino)-5-nitro indane
Figure 881036226_IMG24
In 10 minutes, 2-(N-benzyl-N-methylamino-) indane hydrochloride (2.6 gram) gradation joined and is chilled in-5 ° the nitrosonitric acid (25 milliliters), continued restir 2 minutes, with reaction mixture to frozen water.Water come down in torrents away stay jelly.Jelly is dissolved in the methylene dichloride, with water and saturated sodium bicarbonate aqueous solution washing, dry (MgSO 4), vacuum-evaporation obtains title compound, output 2.4 grams.Sample thief (0.1 gram) is dissolved in the ether, handles with the hydrogenchloride ether.Filter and collect the precipitation that generates, drying obtains the hydrochloride of title compound, fusing point 210-212 °.
Analyze %:
Experimental value: C, 55.2; H, 5.0; N, 11.2;
Calculated value: C 17H 17N 3O 4.HCl. 1/2 H 2O:C, 54.8; H, 5.1; N, 11.3.
′H-N.m.r.（TFAd）：δ＝8.8（s，1H）;8.7（t，1H）;8.35（d，2H）;8.1（d，1H）;7.9（m，1H）;7.6（d，1H）;5.0（d，1H）;4.7（m，1H）;4.6（d，1H）;3.8（m，4H）;3.0（s，3H）.
Preparation 13
5-amino-2-(N-(4-aminobenzyl)-N-methylamino-) indane
(206.8 kPas (30 pounds/inch of room temperature and hydrogen 2)) under, with 2-(N-methyl-N-(4-nitrobenzyl) amino)-solution stirring of 5-nitro indane (2.3 gram) in the ethyl acetate (60 milliliters) that contains 5% palladium/carbon (0.25 gram) 1 hour.Filtration catalizer is extremely done filtrate vacuum-evaporation then.Resistates is made column chromatography purification on silicon-dioxide, to contain the methylene dichloride wash-out of methyl alcohol (0-1%).Merge the fraction that contains product, evaporation obtains oily title compound (1.1 gram), need not make with extra care and can directly use.

Claims (6)

1, the method for the salt of the compound of a kind of preparation structural formula (I) and useful as drug thereof:
Figure 881036226_IMG2
R wherein 1Be hydrogen, C 1-C 4Alkyl, C 1-C 4Alkoxy or halogen;
Each R 2(being identical) is C 1-C 4Alkyl;
X is O or direct key;
N is 1 or 2, is that 0 n is 2 but work as X,
The characteristics of this method are by the following compound of structural formula
Figure 881036226_IMG3
(R wherein 1, X and n are as defined above), with a C 1-C 4Alkyl sulfonyl chloride or acylbromide or a C 1-C 4The alkylsulphonic acid anhydride reactant can change into the product of structural formula (I) salt of useful as drug then.
2,, be characterized in being reflected under the existence of acid acceptor and carry out according to the method for claim 1.
3,, be characterized in that acid acceptor is pyridine, triethylamine, salt of wormwood or sodium bicarbonate according to the method for claim 2.
4,, be characterized in pyridine, carrying out this reaction with methylsulfonyl chloride according to the method for claim 3.
5,, be characterized in 5-methylsulfonyl amido-2-(N-(4-methylsulfonyl amido styroyl)-N-methylamino-according to the method for claim 1) indane is by 5-amino-2-(N-(4-amino-benzene ethyl)-N-methylamino-) indane and methylsulfonyl chloride prepared in reaction in the presence of acid acceptor.
6, a kind of method for preparing medicinal compositions, be characterized in the salt of the compound (as defined in claim 1) of structure formula I or its useful as drug with can make medicinal diluent or carrier and mix mutually.
CN 88103622 1987-03-25 1988-06-17 Preparation method of 1, 2-indane sulfonamide compound with antiarrhythmic drug activity Expired CN1016506B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1055679C (en) * 1995-12-06 2000-08-23 中国药科大学 Phenethylamine derivative with cardiovascular activity
CN103360390A (en) * 2013-07-23 2013-10-23 东南大学 Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application
CN106714976A (en) * 2014-09-25 2017-05-24 拉斯科姆有限公司 Dust and gas ejection valve

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1055679C (en) * 1995-12-06 2000-08-23 中国药科大学 Phenethylamine derivative with cardiovascular activity
CN103360390A (en) * 2013-07-23 2013-10-23 东南大学 Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application
CN103360390B (en) * 2013-07-23 2015-06-17 东南大学 Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application
CN106714976A (en) * 2014-09-25 2017-05-24 拉斯科姆有限公司 Dust and gas ejection valve

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